A novel mitochondrial pool of Cyclin E, regulated by Drp1, is linked to cell density dependent cell proliferation

Abstract

The regulation and function of the crucial cell cycle regulator cyclin E (CycE) remains elusive. Unlike other cyclins, CycE can be uniquely controlled by mitochondrial energetics, the exact mechanism being unclear. Using mammalian cells (in vitro) and Drosophila (in vivo) model systems in parallel, we show that CycE can be directly regulated by mitochondria through its recruitment to the organelle. Active mitochondrial bioenergetics maintains a distinct mitochondrial pool of CycE (mtCycE) lacking a key phosphorylation required for its degradation. Loss of the mitochondrial fission protein dynaminrelated protein 1 (Drp1, SwissProt O00429 in humans) augments mitochondrial respiration and elevates the mtCycE pool allowing CycE deregulation, cell cycle alterations and enrichment of stem cell markers. Such CycE deregulation after Drp1 loss attenuates cell proliferation in low-cell-density environments. However, in high-celldensity environments, elevated MEK-ERK signaling in the absence of Drp1 releases mtCycE to support escape of contact inhibition and maintain aberrant cell proliferation. Such Drp1-driven regulation of CycE recruitment to mitochondria might be a mechanism to modulate CycE degradation during normal developmental processes as well as in tumorigenic events.

Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells

“…DRP1 also demonstrates strong interactions with another cell cycle protein, cyclin E. Although it is unclear how this interaction regulates normal cell cycle progression, it is evident that inhibition of DRP1 leads to increased levels of cyclin E throughout the cell cycle, and especially during the G2/M transition (Mitra et al, 2009; Parker et al, 2015; Qian et al, 2012). This cyclin E buildup causes replication stress in the form of premature entry into a prolonged S-phase, chromosomal instability, and subsequent aneuploidy.…”

“…This cyclin E buildup causes replication stress in the form of premature entry into a prolonged S-phase, chromosomal instability, and subsequent aneuploidy. Some stem cells demonstrate a similar profile of enhanced cyclin E, short G1, and long S-phase, and indeed, progenitor cell markers are upregulated in DRP1-inhibited cells (Parker et al, 2015). Interestingly, concurrent knockdown of the mitochondrial fusion protein, OPA1, with DRP1 abrogates the elevation of cyclin E levels (Qian et al, 2012), suggesting it may be the hyperfused mitochondrial morphology of DRP1-inhibited cells that causes increased cyclin E levels.…”

“…Interestingly, concurrent knockdown of the mitochondrial fusion protein, OPA1, with DRP1 abrogates the elevation of cyclin E levels (Qian et al, 2012), suggesting it may be the hyperfused mitochondrial morphology of DRP1-inhibited cells that causes increased cyclin E levels. It is as yet unclear how mitochondrial morphology controls cyclin E, but intriguingly, a mitochondrial pool of cyclin E, which is not phosphorylated and degraded as the nuclear pool is, was discovered recently (Parker et al, 2015). …”

Morphology of Mitochondria in Syncytial Annelid Female Germ-Line Cyst Visualized by Serial Block-Face SEM

“…e dynamism of mitochondria is the result of two opposing processes: fusion, which leads to their merging into larger mitochondrial networks and ssion, which is the process of separation of an individual mitochondrion from the network. e morphology of mitochondria depends on the balance between these processes [3,[6][7][8][9][10][11][12][13][14][15][16].…”

The mito::mKate2 mouse: A far‐red fluorescent reporter mouse line for tracking mitochondrial dynamics in vivo

“…A previous study suggested that mitochondrial fusion may be instructive for entry into S phase by, at least in part, promoting the buildup of the S phase-promoting protein Cyclin E (Mitra et al, 2009). It is currently unclear how this occurs, but a recent report suggests that a pool of Cyclin E protein is directly recruited to mitochondria (Parker et al, 2015). While these observations and others imply a direct mechanistic link between the cell cycle machinery and mitochondrial fission-fusion proteins (Horn et al, 2011; Mitra et al, 2009; Qiao et al, 2010; Taguchi et al, 2007), there is still much to understand regarding precise cellular and molecular interplay controlling proliferation.…”